Understanding mechanism driven regioselectivity in zirconium-catalysed hydroaminoalkylation: homoallylic amines from conjugated dienes

The unexpected 4,1-hydroaminoalkylation of dienes provides selective access to linear homoallylic amines by zirconium catalysis. This switch from the traditional branched preferred regioselectivity to selective linear product formation using this early transition metal can be attributed to π-allyl intermediates. The reactivity of these isolated intermediates on a sterically accessible and coordinatively flexible chelating bis(ureate) Zr(iv) complex confirmed reversible C–C bond formation in hydroaminoalkylation catalysis.


Synthesis of 8-Ph:
To a ⁓1 mL C6D6 solution of complex 6-Ph (0.273 g, 0.38 mmol), excess isoprene (> 8 equiv) was added using a micropipette.Heating the reaction to 65 °C gradually resulted in a change from colorless to yellow.The reaction was found to be complete after 16 h by 1 H NMR spectroscopy.Next, the solution was transferred to a 20 mL vial and the volatiles were removed in vacuo.The resulting yellow oil was redissolved in ⁓1 mL toluene and the solution was cooled down to −35 °C overnight, during which time yellow crystals of complex 8-Ph (0.199 g, 75% yield) were formed as a mixture of diastereomers.
Young tube and a t = 0 h 1 H NMR spectrum was obtained before heating to 145 °C for 48 h.After the reaction, a solution of 1,2,4,5-tetramethylbenzene in ⁓0.15 mL C6D6 was then transferred to the reaction mixture and a 1 H NMR spectrum was obtained for NMR yield determination.The obtained yield was determined as the average yield from two duplicate experiments.The ratio of 1/(E)-2 and the ratio of (E)-1/(Z)-1 was obtained from the integrations of the diagnostic benzylic resonances of each compound in the 1 H NMR spectrum.These ratios were further corroborated by GC-MS analysis.The chemical shifts for (E)-1 were consistent with those previously reported in the literature. 7droaminoalkylation of 1-phenyl-1,3-butadiene catalyzed by in situ formed bis(ureate) zirconium catalyst: To a small vial containing bis(urea) proligand L1 (0.007 g, 0.02 mmol), a solution of Zr(NMe2)4 (0.006 g, 0.02 mmol) in ⁓0.25 mL C6D6 was added and mixed thoroughly to form the precatalyst.Then, solutions of N-benzylaniline (0.037 g, 0.20 mmol) and 1-phenyl-butadiene (0.030 g, 0.023 mmol) in ⁓0.25 mL C6D6 were added separately using a total of ⁓0.25 mL C6D6 for quantitative transfer.The resulting solution was transferred into a J. Young tube and a t = 0 h 1 H NMR spectrum was obtained before heating to 145 °C for 48 h.After the reaction, a solution of 1,2,4,5-tetramethylbenzene in ⁓0.15 mL C6D6 was then transferred to the reaction mixture and a 1 H NMR spectrum was obtained for NMR yield determination.

Hydroaminoalkylation of 1-phenyl-1,3-butadiene catalyzed by Ti(NMe2)4:
To a small vial containing a solution of Ti(NMe2)4 (0.005 g, 0.02 mmol) in ⁓0.25 mL C6D6, solutions of N-benzylaniline (0.037 g, 0.20 mmol) and 1-phenyl-butadiene (0.030 g, 0.023 mmol) in ⁓0.25 mL C6D6 were added separately using a total of ⁓0.25 mL C6D6 for quantitative transfer.The resulting solution was transferred into a J. Young tube and a t = 0 h 1 H NMR spectrum was obtained before heating to 145 °C for 48 h.After the reaction, a solution of 1,3,5-trimethoxybenzene in ⁓0.15 mL C6D6 was then transferred to the reaction mixture and a 1 H NMR spectrum was obtained for NMR yield determination.The obtained yield was determined as the average yield from two duplicate experiments.The ratio of 1/(E)-2 and the ratio of (E)-1/(Z)-1 was obtained from the integrations of the diagnostic benzylic resonances of each compound in the 1 H NMR spectrum.
These ratios were further corroborated by GC-MS analysis.For characterization of the major product (E)-2, see experiment below.

Hydroaminoalkylation of 1-phenyl-1,3-butadiene catalyzed by in situ formed ureate titanium catalyst:
To a small vial containing the urea proligand L2 (0.007 g, 0.02 mmol), a solution of Ti(NMe2)4 (0.005 g, 0.02 mmol) in ⁓0.25 mL C6D6 was added and mixed thoroughly to form the precatalyst.Then, solutions of N-benzylaniline (0.037 g, 0.20 mmol) and 1-phenyl-butadiene (0.030 g, 0.023 mmol) in ⁓0.25 mL C6D6 were added separately using a total of ⁓0.25 mL C6D6 for quantitative transfer.The resulting solution was transferred into a J. Young tube and a t = 0 h 1 H NMR spectrum was obtained before heating to 145 °C for 48 h.After the reaction, a solution of 1,3,5-trimethoxybenzene in ⁓0.15 mL C6D6 was then transferred to the reaction mixture and a 1 H NMR spectrum was obtained for NMR yield determination.
The obtained yield was determined as the average yield from two duplicate experiments.The ratio of 1/(E)-2 and the ratio of (E)-1/(Z)-1 was obtained from the integrations of the diagnostic benzylic resonances of each compound in the 1 H NMR spectrum.These ratios were further corroborated by GC-MS analysis.For characterization of the major product (E)-2, the crude reaction mixture without internal standard was quenched with ⁓2 mL DCM and filtered through diatomaceous earth.The volatiles were then removed in vacuo and the resulting residue was purified by silica column chromatography (hexanes/ethyl acetate) to give (E)-2 in a 13% isolated yield. 1
Then, a t = 0 h 1 H NMR spectrum was obtained before heating to 145 °C for 48 h.After the reaction, a solution of 1,3,5-trimethoxybenzene in ⁓0.15 mL C6D6 was then transferred to the reaction mixture and a 1 H NMR spectrum was obtained for NMR yield and regioselectivity determination.The obtained yield and regioselectivity was determined as the average from two duplicate experiments.The regioselectivity toward (E)-5 was obtained from the integrations of the diagnostic benzylic resonances of each compound in the 1 H NMR spectrum.For characterization of the major product (E)-4, the crude reaction mixture without internal standard was quenched with ⁓2 mL DCM and filtered through diatomaceous earth.The volatiles were then removed in vacuo and the resulting residue was purified by silica column chromatography (hexanes/ethyl acetate) to give (E)-4 in a 19% isolated yield. 1

Hydroaminoalkylation of isoprene catalyzed by in situ formed bis(ureate) zirconium catalyst:
To a small vial containing bis(urea) proligand L1 (0.007 g, 0.02 mmol), a solution of Zr(NMe2)4 (0.006 g, 0.02 mmol) in ⁓0.25 mL C6D6 was added and mixed thoroughly to form the precatalyst.After 20 min, a solution of N-benzylaniline (0.037 g, 0.2 mmol) was added to the precatalyst solution, using a total of ⁓0.25 mL C6D6 for quantitative transfer.The solution was then transferred into a J. Young tube, and excess isoprene (>8 equiv) was then added using a micropipette.A t = 0 h 1 H NMR spectrum was obtained before heating to 145 °C for 48 h.After the reaction, a solution of 1,3,5-trimethoxybenzene in ⁓0.15 mL C6D6 was then transferred to the reaction mixture and a 1 H NMR spectrum was obtained for NMR yield determination.
The obtained yield was determined as the average yield from two duplicate experiments.GC-MS analysis further supported the formation of 7 as the sole regioisomer.For complete characterization of 5, see the experiment below "Stoichiometric product release from complexes 8-Ph".
Stoichiometric product release from complexes 8-Ph: A ⁓0.75 mL C6D6 solution of complex 8-Ph (syn/anti mixture) (0.100 g, 0.14 mmol) was quenched with ⁓5 mL DCM and filtered through diatomaceous earth.The volatiles were then removed in vacuo and the resulting residue was purified by silica column chromatography (hexanes/ethyl acetate in a 50:1 volume ratio) to obtain compound 5 as a yellow oil (0.024 g, 68% yield). 1  Crossover experiment between complex 8-Ph and 1-phenyl-1,3-butadiene: To a ⁓0.5 mL C6D6 solution of complex 8-Ph (syn/anti mixture) (0.020 g, 0.029 mmol, a solution of 1-phenyl-1,3-butadiene in ~0.25 mL C6D6 was added and mixed thoroughly before transferring to a J.Young tube.Then, a t = 0 h 1 H NMR spectrum was obtained before heating to 90 °C for 16 h.After this time, the reaction was left to cool down to room temperature and a 1 H NMR spectrum was obtained, revealing 99% conversion to complexes 7-Ph(syn) and 7-Ph(anti) in a 1 : 2.7 ratio.

Crystallographic details
A summary of the crystallographic data for compounds 7-Si, 7-Ph(syn), and 8-Ph(syn) is shown in Table S1.The automatic data collection strategy, indexing and integration were carried out using the Bruker APEX3 Crystallography Software Suite.Using Olex2, 8 the structures were solved with the ShelXT 9 structure solution program using Intrinsic Phasing and the structures were refined using the ShelXL 10 refinement package using the Least Squares method.
a Resonance found through HMBC NMR.